title: PRMT5-mediated histone H4 arginine-3 symmetrical dimethylation marks chromatin at G + C-rich regions of the mouse genome.
abstract: Symmetrical dimethylation on arginine-3 of histone H4 (H4R3me2s) has been reported to occur at several repressed genes, but its specific regulation and genomic distribution remained unclear. Here, we show that the type-II protein arginine methyltransferase PRMT5 controls H4R3me2s in mouse embryonic fibroblasts (MEFs). In these differentiated cells, we find that the genome-wide pattern of H4R3me2s is highly similar to that in embryonic stem cells. In both the cell types, H4R3me2s peaks are detected predominantly at G + C-rich regions. Promoters are consistently marked by H4R3me2s, independently of transcriptional activity. Remarkably, H4R3me2s is mono-allelic at imprinting control regions (ICRs), at which it marks the same parental allele as H3K9me3, H4K20me3 and DNA methylation. These repressive chromatin modifications are regulated independently, however, since PRMT5-depletion in MEFs resulted in loss of H4R3me2s, without affecting H3K9me3, H4K20me3 or DNA methylation. Conversely, depletion of ESET (KMT1E) or SUV420H1/H2 (KMT5B/C) affected H3K9me3 and H4K20me3, respectively, without altering H4R3me2s at ICRs. Combined, our data indicate that PRMT5-mediated H4R3me2s uniquely marks the mammalian genome, mostly at G + C-rich regions, and independently from transcriptional activity or chromatin repression. Furthermore, comparative bioinformatics analyses suggest a putative role of PRMT5-mediated H4R3me2s in chromatin configuration in the nucleus.
authors.affiliation: Institute of Molecular Genetics (IGMM), CNRS UMR 5535, University of Montpellier, 1919 route de Mende, 34293 Montpellier, Laboratoire Epigénétique et Destin Cellulaire, UMR7216, CNRS, Université Paris Diderot, 35 rue Hélène Brion, 75013 Paris, France and Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Girardot
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Hirasawa
authors.forename: Salim
authors.initials: S
authors.lastname: Kacem
authors.forename: Lauriane
authors.initials: L
authors.lastname: Fritsch
authors.forename: Julien
authors.initials: J
authors.lastname: Pontis
authors.forename: Satya K
authors.initials: SK
authors.lastname: Kota
authors.forename: Doria
authors.initials: D
authors.lastname: Filipponi
authors.forename: Eric
authors.initials: E
authors.lastname: Fabbrizio
authors.forename: Claude
authors.initials: C
authors.lastname: Sardet
authors.forename: Felix
authors.initials: F
authors.lastname: Lohmann
authors.forename: Shilpa
authors.initials: S
authors.lastname: Kadam
authors.forename: Slimane
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
mesh_terms: D000483:Alleles; D000818:Animals; D001120:Arginine / Q000378:metabolism*; D002478:Cells, Cultured; D002843:Chromatin / Q000201:enzymology*; D019175:DNA Methylation; D005347:Fibroblasts / Q000201:enzymology; D020862:GC Rich Sequence; D016678:Genome; D018392:Genomic Imprinting; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases
chemical_list: D002843:Chromatin; D006657:Histones; D001120:Arginine; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases